Download Detrimental impact of microbiota-accessible carbohydrate deprived

Mini Review
published: 12 May 2017
doi: 10.3389/fimmu.2017.00548
Detrimental impact of MicrobiotaAccessible Carbohydrate-Deprived
Diet on Gut and immune
Homeostasis: An Overview
Claire Immediato Daïen1,2,3, Gabriela Veronica Pinget1,2, Jian Kai Tan4 and
Laurence Macia1,2,4*
Nutritional Immunometabolism Node Laboratory, Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia,
School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia, 3 Institut de génétique moléculaire de
Montpellier, UMR5535, Montpellier University, Montpellier, France, 4 Infection and Immunity Program, Department of
Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
1
2
Edited by:
Caroline Elizabeth Childs,
University of Southampton, UK
Reviewed by:
Elizabeth P. Ryan,
Colorado State University, USA
Mourad Aribi,
University of Tlemcen, Algeria
*Correspondence:
Laurence Macia
[email protected]
Specialty section:
This article was submitted to
Nutritional Immunology,
a section of the journal
Frontiers in Immunology
Received: 11 January 2017
Accepted: 24 April 2017
Published: 12 May 2017
Citation:
Daïen CI, Pinget GV, Tan JK and
Macia L (2017) Detrimental Impact of
Microbiota-Accessible CarbohydrateDeprived Diet on Gut and Immune
Homeostasis: An Overview.
Front. Immunol. 8:548.
doi: 10.3389/fimmu.2017.00548
Dietary fibers are non-digestible polysaccharides functionally known as microbiota-accessible carbohydrates (MACs), present in inadequate amounts in the Western diet.
MACs are a main source of energy for gut bacteria so the abundance and variety of
MACs can modulate gut microbial composition and function. This, in turn, impacts host
immunity and health. In preclinical studies, MAC-deprived diet and disruption of gut
homeostasis aggravate the development of inflammatory diseases, such as allergies,
infections, and autoimmune diseases. The present review provides a synopsis on the
impact of a low-MAC diet on gut homeostasis or, more specifically, on gut microbiota,
gut epithelium, and immune cells.
Keywords: dietary fiber, microbiota-accessible carbohydrates, immunity, gut homeostasis, gut barrier, gut
microbiota, epithelium
INTRODUCTION
In recent decades, the prevalence of non-communicable diseases, such as allergies, autoimmune,
and inflammatory diseases has increased drastically in Western lifestyle countries. For instance, the
incidence of asthma in Swedish schoolchildren doubled between 1979 and 1991 (1), the incidence
of multiple sclerosis in Germany (Lower Saxony) doubled from 1969 to 1986 (2), and the incidence
of Crohn’s disease in northern Europe more than tripled from the 1950s to the 1990s (3).
Although largely unexplained, these increases are likely to have a strong environmental
component (4, 5). Dramatic lifestyle changes followed the industrial revolution, among which a
nutritional transition from a traditional diet to the Western diet (6). This diet consists of heavily
processed foods, rich in fat, sugar, protein, and a variety of additives, while remaining low in
micronutrients and dietary fiber (7). While most nutrients are absorbed in the duodenum during
the digestion process, dietary fiber remains intact until it reaches the colon, which is inhabited by
trillions of bacteria known as the gut microbiota (8, 9). Dietary fibers are complex carbohydrates
of plant origin, broken down by specialized enzymes produced by gut bacteria but indigestible by
the host (10). They have recently been redefined as microbiota-accessible carbohydrates (MACs)
Abbreviations: DSS, dextran sodium sulfate; MACs, microbiota-accessible carbohydrates; SCFAs, short-chain fatty acids.
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Figure 1 | Schematic representation of impact of low dietary microbiota-accessible carbohydrates (MACs) on microbiota and gut homeostasis.
Consumption of low dietary MACs leads to decreased gut bacterial diversity with outgrowth of mucus-degrading bacteria and decreased levels of MAC-degrading
bacteria. The mucus layer will thus become thinner exacerbated by reduced production of Muc2 due to reduced short-chain fatty acids (SCFAs) production.
This decrease in production of SCFAs also impairs GPR43 activation on epithelial cells leading to increased production of proTh2 cytokine TSLP and decreased
activation of NLRP3, and thus, decreased production of epithelial healing cytokine IL-18. Low SCFAs also impair epithelial barrier function as shown by decreased
transepithelial resistance (TER), leading to increased bacterial product translocation into the lamina propria, triggering inflammatory reactions. Finally, due to their key
role in immune function, low SCFAs impair regulatory T cell (Treg), Th1 cell, and Th17 cell, while enhancing T helper 2 (Th2) development. Decreased direct activation
of B-cells and indirect activation through decreased T follicular helper cells impair IgA and IgG production.
and represent the major energy source for colonic bacteria (11).
The recommended daily intake of dietary fiber is at least 30 g,
although, on average, those on the Western diet only consume
15 g (7). In a cohort of 219,123 men and 168,999 women, Park
et al. studied the association between intake of dietary fiber,
ranging from 11 to 29 g/day, and death from cardiovascular,
infectious, and respiratory diseases, with a 9-year follow-up
(12). This study shows that dietary fiber intake was significantly
associated with a 22% decrease in mortality rate in both genders (multivariate relative risk comparing the highest with the
lowest quintile). Areas described as “food deserts,” defined by
the absence of healthy food availability in a one mile radius,
are characterized by low-MAC consumption and an increased
incidence of asthma in children (13).
People in traditional societies, where fiber intake can reach
50–120 g/day, are associated with a much more diverse gut microbiota when compared with people in Western countries (14–16).
A diverse microbiome is associated with “good health,” while low
diversity and dysbiosis have been correlated to diseases highly
prevalent in Western society, such as obesity, type 2 diabetes,
inflammatory bowel diseases, rheumatoid arthritis, and asthma
(17–20).
Short-chain fatty acids (SCFAs), namely, acetate, butyrate,
and propionate, are released by gut bacteria during fermentation
of dietary fibers. These can bind to the G protein-coupled receptors such as GPR41, GPR43, and GPR109a that are expressed
Frontiers in Immunology | www.frontiersin.org
by both immune and non-immune cells (4, 9, 21, 22). They are
also known to inhibit histone deacetylases (HDACs) activity
in immune cells, promoting anti-inflammatory cells (5, 23).
The immune effects of SCFAs are further detailed in Section
“Impact of Low Dietary MACs on Immune Cells and Disease
Development.” SCFAs play a key role in health and disease and
are found at lower concentrations in populations consuming a
Western diet when compared to those consuming a traditional
diet (14). Therefore, low bacterial diversity, as well as low SCFAs,
could partially explain the rise of non-communicable diseases in
Western countries (24, 25).
Microbiota-accessible carbohydrates are the main source of
carbon for colonic bacteria and favor an increase in beneficial
bacteria. The composition and function of the gut microbiota is
thus highly dependent on the availability of MACs. While the
beneficial impact of supplementation with dietary MACs on gut
microbiota, host metabolism, and immunity has been reported
before, the present review will focus on the deleterious impact
of low-MAC consumption on gut homeostasis, immunity, and
disease development as illustrated in Figure 1.
IMPACT OF LOW MACs ON GUT
MICROBIOTA
Diet composition, particularly the availability of MACs, has a
major impact on gut microbiota.
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Low Dietary MACs Promote MucusDegrading Bacteria
on low-MAC feeding, a high-MAC diet was fully inefficient
at restoring bacterial diversity, which could only be overcome
by the administration of high-MAC microbiota in addition to
the high-MAC diet. The Western diet is not only deprived of
MACs but also has macronutrient imbalance and micronutrient
deprivation, which suggests that in humans, stable dysbiosis
over three to four generations could be the best-case scenario,
although quicker irreversible dysbiosis may be closer to reality.
While this study did investigate the impact of such a diet on
disease development, we also demonstrate that reconstitution
of germ-free mice with microbiota from mice fed on an MACdeprived diet was associated with more severe colitis and food
allergy (4, 22). This suggests that dysbiotic microbiota due to low
MACs can exacerbate non-communicable disease development.
Depending on their enzymatic machinery, gut bacteria can
either extract carbon from dietary MACs or endogenous mucus
as source of energy (26). The mucus layer is produced by specialized epithelial cells, the goblet cells and is characterized by
a glycoprotein-rich layer that overlies the gut epithelium. This
layer represents the first line of defense against commensal
and pathogenic bacteria (27). Two subsets of gut bacteria can
degrade the mucus, either bacteria extracting their energy
exclusively from the mucus: the mucin-degrading specialists (i.e.,
Akkermansia muciniphila) or from both the mucus and dietary
MACs: the mucin-degrading generalists (i.e., Bacteroides caccae)
(28). Under low dietary MAC conditions, mucin-degrading generalists shift from utilization of dietary polysaccharides to mucus
glycan (28). It was recently shown that MAC deficiency leads to a
rapid increase in abundance of mucin-degrading bacteria (both
mucin-degrading specialists and generalists) and a decrease in
MAC-degrading species (29). Transcriptomic analysis revealed
that MAC availability in the diet could modulate the expression
of glycoside hydrolases and polysaccharide lyases, enzymes
specialized in complex polysaccharide digestion (26). Under low
dietary MAC conditions, these mucus-degrading enzymes are
upregulated and vice versa.
Some bacteria have also evolved ways to extract and release
polysaccharides from their own cell wall through the activation
of outer surface glycoside hydrolases. These membrane polysaccharides can then become available for surrounding bacteria,
in a mechanism called cross-feeding (30). Bacteroides ovatus,
an important MAC-degrading bacterium, is a crucial source of
nutrients for other bacteria, via cross-feeding (30). Hence, dietary
MAC content will not only impact mucus or MAC-dependent
bacteria but also the growth of such cross-fed bacteria.
The microbial changes observed in studies using MACrestricted diets and described in this review (4, 5, 22, 26, 29, 31,
32) are summarized in Table 1. The most consistent changes
observed in a low-MAC diet compared to a high-MAC diet, are
an increase in Proteobacteria and a decrease in Bacteroidetes, as
well as a decline in bacterial diversity.
IMPACT OF LOW DIETARY MACs ON GUT
EPITHELIUM
The gut epithelium is a dynamic barrier ensuring the physical
separation between the host and the gut microbiota while also
enabling their communication (33). Epithelial integrity is a
pillar of both gut and overall health. Indeed, increased gut permeability, linked to Western diet consumption and dysbiosis,
facilitates translocation of bacterial products in the host (8).
This might be a trigger for allergic, autoimmune, or endocrine
diseases (25).
Low Dietary MACs Contribute to
Decreased Epithelial Integrity
Bacterially derived SCFAs ensure epithelial integrity by increasing transepithelial resistance (34), as well as promoting mucus
secretion (35). SCFAs increase prostaglandin secretion by subepithelial myofibroblasts, which, in turn, promote epithelial mucin
expression, a key component of the mucus layer (36). Butyrate,
but neither acetate nor propionate, upregulated colonic mucin
expression in vitro, by inhibiting HDAC activity (37). SCFAs
have also been recently found to be critical for epithelium repair,
through the direct activation of NLRP3 inflammasome in gut epithelial cells, leading to release of IL-18 (4). NLRP3 inflammasome
activation is protective in a murine model of colitis induced by
dextran sodium sulfate (DSS) (38). Mice fed on an MAC-deprived
diet had significantly less IL-18, and worse DSS-induced colitis
(4, 39). Inflammasome activation is a two-step process involving
both a priming and a trigger phase (39). While these phases are
well characterized in macrophages, they remain elusive in epithelial cells. It was recently shown that fecal extracts, containing
various microbial associated molecular patterns (MAMPs) could
prime the NLRP3 inflammasome, and that acetate could trigger
this pathway by inducing cell hyperpolarization secondary to
increased intracellular Ca2+. Interestingly, fecal supernatants from
low MAC-fed mice were less potent in priming NLRP3 inflammasome compare to those from high MACs probably due to the
different MAMPs present (4). While most studies focus on SCFAs
as critical in promoting beneficial effects of MACs in diseases, it
is important to note that beneficial changes in the microbiota by
itself is also critical, as treatment with SCFAs in drinking water
only partially recapitulates the effects of MACs (4, 22).
Low Dietary MACs Lead to Decreased
Bacterial Diversity with Irreversible Loss
of Bacterial Strains
A recent breakthrough has been made in the impact of low
dietary MACs on gut microbiota (26). Mice with a humanized microbiota, fed on a low-MAC diet for 7 weeks, had
significantly decreased bacterial diversity, which was never
fully restored despite switching their diet to a high-MAC diet
for the following 15 weeks. This phenomenon is described as
“scars” of the microbiota, characterized by the disappearance of
specific operational taxonomic units, while other bacteria are
more resilient and able grow back to their initial levels. Over
three generations on low-MAC feeding, the gut microbiota was
stably “dysbiotic,” with a decline in taxa, mostly of Bacteroidales,
and a marked loss of the glycoside hydrolase repertoire, the
enzymes necessary to process MACs. By the fourth generation
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Table 1 | Microbiota changes in mice fed on low dietary microbiota-accessible carbohydrates (MACs).
Studies
Mice studied Method used for gut
analysis
Low-MAC diet
Comparator diet
Changes observed in low-MAC diet group
Decrease
Increase
Desai et al.
(29)
Germ-free
Swiss
Webster mice
colonized
by synthetic
human
microbiota
Illumina sequencing of
16S rRNA genes (V4
region)
0% fiber. Starch and
High MACs: 4.2% crude Fiber-degrading species:
maldodextrin replaced with fiber (14.6% ND fiber;
Bacteroides ovatus;
glucose (Harlan TD.140343) 5.3% AD fiber) (LabDiet Eubacterium rectale
5010)
Mucin specialists
(Akkermansia
muciniphila; Barnesiella
intestinihomnis) and
mucin generalists
(Bacteroides
thetaiotaomicron;
Bacteroides caccae)
Sonnenburg
et al. (26)
Germ-free
Swiss
Webster mice
colonized
by human
microbiota
Illumina sequencing of
16S rRNA genes (V4
region)
Carbohydrates from
sucrose (31%), corn starch
(31%), and cellulose (5%)
(Harlan TD.86489)
High-MAC (LabDiet
5010)
Diversity (Shannon index), Clostridiales
Bacteroidales sp.
Macia et al. (4) C57BL/6
mice
Roche 454 sequencing
of 16s rRNA gene (V2–
V3 region)
Modification of AIN93G. Fiber, starch, and
dextrinized starch replaced
by dextrose (SF09-028)
devoid of fiber or starch
High MACs:
modification of AIN-93G
enriched in guar gum
(20%) and cellulose
(20%) (SF11-029)
Prevotellaceae family
Bacteroidaceae;
Oscillibacter sp.
Thorburn et al. C57Bl6 and
(5)
BALB/c mice
Roche/454 FLX
Crude fiber 0%; AD fiber
sequencing of 16S rRNA 0% (SF09-028)
genes (V1–V3 region)
High MACs Gel crisp
starch. Crude fiber
3.2%; AD Fiber 4.2%
(SF11-025)
Diversity (Shannon
index), observed
species and equability
(chao1); Bacteroidetes,
Bacterioidaceae, and
Bacteroidales
Proteobacteria phylum,
especially: Pandoraea,
Burkholderiaceae
Tan et al. (22)
C57BL/6
mice
Illumina sequencing of
16S rRNA genes (V3–V4
region)
Modification of AIN-93G
devoid of fiber or starch
(SF09-028)
High MACs (SF11-029)
Proteobacteria,
Deltaproteobacteria, and
Desulfovibrionales
Firmicutes bacilli,
Lactobacillales
Kim et al. (31)
C57BL/6
mice
qPCR analysis of 16S
rRNA gene sequences
0% fiber
High MACs: 15% of
pectin and inulin (1:1)
Bacteroidetes phylum
Proteobacteria phylum
Trompette
et al. (32)
C57BL/6
female mice
Roche/454 FLX
<0.3% fiber (Provimi Kliba
sequencing of 16S rRNA diet 2122)
genes (V1–V3 region)
Normal chow 4% fiber
(Provimi Kliba diet 3202)
Diversity (Shannon index)
and richness (operational
taxonomic units)
Proteobacteria phylum
AD, acid detergent; ND, neutral detergent.
Microbiota-accessible carbohydrate-induced microbiota
changes can also directly impact epithelial integrity. As described
above, under low-MAC conditions, some bacteria use the mucus
layer as a source of energy. This phenomenon thins the mucus
layer and impairs the epithelial barrier. This low MAC-induced
gut permeability was associated with increased susceptibility to
the epithelium-targeting pathogen Citrobacter rodentium suggesting that dietary MACs are key in fighting gastrointestinal
infections (29).
Altogether, these results illustrate the detrimental impact of
a low-MAC diet on the gut microbiota–epithelium–immune
axis.
IMPACT OF LOW DIETARY MACs ON
IMMUNE CELLS AND DISEASE
DEVELOPMENT
This section highlights several key studies examining the opposing effects of MAC deprivation vs. enrichment on the immune
system. Diet composition, as well as changes in gut microbiota,
can profoundly impact immune function, as a vast majority of
immune cells are located in the gut lamina propria (41). Significant
advances have been made in recent years to understand the impact
of MACs on the immune system. However, much of the focus has
been on high-MAC diets with little insight on the impact of MAC
deprivation on the immune system. A comprehensive survey of
MAC enrichment vs. deprivation is essential for deciphering how
specific immune pathways are regulated under varied dietary
habits, and whether MACs plays a preventative or corrective role
in various diseases.
Low Dietary MACs Modify Epithelium
Cytokine Expression
While MACs have the ability to affect the bacterial–epithelium
interaction, they can also affect the epithelial–immune interaction
(22, 40). Mice fed on a low-MAC diet had increased expression of
epithelial tslp, a cytokine known to direct the immune response
toward T helper 2 (Th2), involved in allergy development. On the
other hand, high MACs, through release of SCFAs and subsequent
activation of GPR43 in the epithelium, had the opposite effect
(22). Moreover, low IL-18 mediated by low-MACs, might affect
immune cells such as natural killer cells, which remain unexplored.
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Dendritic Cells
as mice fed on an MAC-deficient diet have defective homeostatic
and pathogen-specific antibody responses (31). In contrast,
mice fed on a high-MAC diet had significantly enhanced IgA
production compared to mice fed a no-MAC diet (22, 31). HighMAC feeding increased T follicular helper response marked
by increased germinal center activities in the Peyer’s patches,
as well as IgA+ B cells in the small intestine (22). These effects
on B cells are both linked to MAC-induced changes in the gut
microbiota composition (22) and to the production of SCFAs as
they support B cell antibody production by promoting plasma
cell differentiation (31). Kim et al. also demonstrated that MAC
deficiency increased C. rodentium disease burden due to reduced
antibody production and diminished clearance of C. rodentium.
Deficiency in dietary MACs may therefore alter B cell response
and predispose to bacterial infection burden.
Short-chain fatty acids elicit numerous effects on the function
and hematopoiesis of dendritic cells. Propionate was shown to
alter DC precursors in the bone marrow, which attenuated their
ability to promote Th2 effector cells in the lungs (32). Indeed,
mice fed on a low-MAC diet developed exacerbated allergic
airway inflammation.
Short-chain fatty acid, particularly acetate and butyrate, could
also affect tolerogenic DC function (22). Under no-MAC feeding
conditions, CD103+ dendritic cells had a diminished ability to
generate a tolerogenic regulatory T cell (Treg), compared to highMAC feeding conditions. Mice fed on a no-MAC diet exhibited
severe clinical anaphylaxis compared to mice fed on a high-MAC
diet in a model of food allergy. Protection by high-MAC diet was
mediated through the enhancement of retinal-dehydrogenase
activity in CD103+ dendritic cells, an enzyme required for the
conversion of vitamin A into retinoic acid to promote Treg differentiation. As such, the protective effects of high-MACs on food
allergy were abrogated in the absence of vitamin A in diet. Both
the SCFA receptors such as GPR43 and GPR109A were indispensable for high-MAC-mediated protection against food allergy.
Interestingly, mice fed on a control MAC diet (equivalent to
recommended amount of 14 g/1,000 kcal/day) exhibited similar
severity to food allergy to mice fed on a no-MAC diet. This suggests that, in this instance, high levels of MACs are necessary for
optimal protection against development of food allergies rather
than the recommended amount (22).
However, despite these beneficial effects of SCFAs in allergy,
the role of SCFAs in tolerance is not clear; as a recent study has
highlighted both beneficial and detrimental effects of SCFAs
in experimental autoimmune diseases and antibody-induced
arthritis, respectively (42). The mechanisms behind these differential effects in autoimmunity are yet to be determined.
Neutrophils
Dietary MACs were first linked to leukocyte migration by
identification of SCFA receptor GPR43 as a neutrophil chemoattractant (47, 48). SCFAs were shown to elicit GPR43-dependent
activation of PKB, p38, and ERK in neutrophils leading to their
migration through polycarbonate filters toward a source of acetate, propionate, or butyrate (48). On the other hand, absence of
GPR43 exacerbated recruitment of neutrophils in DSS-induced
acute colitis, chronic colitis, and in a model of systemic LPS
challenge (47, 49, 50), suggesting differential roles for GPR43 on
neutrophil migration under inflammatory vs. non-inflammatory
conditions.
It has also been shown that a low-MAC diet exacerbated
gout in a mouse model and that acetate promoted resolution
of neutrophilic inflammation in a GPR43-dependent manner.
This resolution of inflammation was associated with increased
caspase-mediated neutrophil apoptosis in MSU-challenged
mice (51). Thus, deficiency in MACs might not only exacerbate inflammatory reaction but also impair inflammatory
resolution.
T Cells
Short-chain fatty acids have a broad impact on T cell function by
directly promoting the differentiation of naïve T cells into Treg
(23, 43, 44), Th1, and Th17 (45) and indirectly inhibiting Th2
differentiation (22).
Acetate has been shown to promote Treg differentiation by
inhibiting the histone deacetylase HDAC9 in T cells, stimulating transcription of Foxp3 (5). This was a key mechanism in the
protection against allergic airway inflammation as mice fed on noMAC diet developed exacerbated disease. Treatment with acetate
was also protective independently of GPR43, suggesting that the
beneficial effects of MACs were solely based on HDAC inhibition.
Both acetate and butyrate promote the induction of Th1 and
Th17 T cells. These effects were also dependent on HDAC inhibition and activation of the pathway mTOR–ribosomal protein S6
kinase, but independent of GPR41 and GPR43 signaling (45).
Induction of Th1, Th17, and IL-10-producing T-cells by acetate
and butyrate might be key in the beneficial effects of high MACs
in C. rodentium infections (46).
CONCLUSION
Food processing has significantly decreased the amount of MAC
content in the Western diet, when compared to the contents of
the ancestral hominin diet (7). As discussed above, low-MAC
consumption not only has detrimental impacts on gut microbiota
in particular but also on the host as a whole. It favors the development of diseases and increases mortality, as shown in preclinical
and clinical studies (5, 9, 52). Low consumption of MACs over
generations leads to the complete disappearance of beneficial
bacterial strains in a preclinical study (26). While such study
has not been carried out in humans, it is known that, similar to
mice, the consumption of a diet low in MACs decreases bacterial
diversity. This seems to suggest that long-term-reduced MAC
consumption over generations will likely also have detrimental
effects in humans. The only treatment able to correct this “scarred
microbiota” was combined dietary and probiotic interventions.
This might explain the low efficacy of probiotic-exclusive treatments in humans, as probiotics may not grow in a dysbiotic environment. Thus, dietary interventions alongside administration
B Cells
Microbiota-accessible carbohydrates appear to be pivotal regulators of antibody response both locally in the gut and systemically
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ACKNOWLEDGMENTS
of beneficial bacterial strains could be a cost effective treatment
to manage most non-communicable Western lifestyle diseases.
Extensive research still needs to be done to determine (1) what
types of MACs are most efficient at diversifying the microbiota
and promoting production of SCFAs and (2) how much MACs
should be consumed to optimize maintenance of health, or to
treat different types of inflammatory diseases.
The authors thank Pedro Telleria Teixeira and Sumaiya Hoque for
revising the manuscript.
FUNDING
Work related to this review is funded in part by a’Beckett
Foundation (to LM), Henry Langley Fellowship (to CD),
University of Sydney Kickstart Grant (to LM), NHMRC
APP1068890 (to LM), and APA (to JT and GP).
AUTHOR CONTRIBUTIONS
The review was cowritten by CD, GP, JT, and LM.
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Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
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